Long-Term Complication Risk After Very High Dose Thoracic Radiotherapy

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Although significant gains have been made in the treatment of non-small cell lung cancer (NSCLC) with the use of chemoradiation, patients as a whole still do poorly, with a significant number still failing locally. In order to attempt to increase local control, escalating doses of thoracic radiation has been employed. However, as radiation dose increases, risk of toxicity to normal tissues also increases. A hypothesis has been postulated that TGF-B levels correlate with the chances of developing late toxicities. This study reports on the probability of developing late toxicity with increasing doses of thoracic radiation and attempts to determine the feasibility of using plasma TGF-B to select patients to escalate doses.

Materials and Methods

38 patients were enrolled in this prospective study

All patients were either Stage III or inoperable Stage I-II NSCLC

No concurrent chemotherapy was permitted

1.6 Gy BID radiation was used

All patients received 45 Gy to the GTV + ipsilateral hilum + mediastinum followed by conedown to include the GTV + gross nodal disease to a dose of 57.6 Gy. All patients were then treated to 73.6 Gy to the GTV itself.

After 73.6 Gy, TGF-B levels were monitored. If TGF-B levels were normal, dose escalation to 80 Gy or 86.4 Gy was performed.

Median follow up was 16 months

Grade 3-5 late toxicity was noted in all patients

Results

24 patients stopped at 73.6 Gy due to escalation of TGF-B levels. 8 patients were treated to 80 Gy and 6 patients were treated to 86.4 Gy

In the 86.4 Gy group, 1 patient developed late esophageal toxicity and 1 patient developed late pulmonary toxicity

5/7 of the late toxicities noted developed within the first 11 months

There were 8 long term survivors (out of 38 patients), all in the control group

Author's Conclusions

Long-term survivors have a significant risk of developing Grade 3-5 complications, with the dose limiting organ not necessarily the esophagus

Increased TGF-B levels at the end of treatment may identify those patients at greatest risk

Consideration should be given for studies to be done investigating radioprotectors in those patients in which dose escalation is planned

Clinical/Scientific Implications

Dose escalation of thoracic radiation is one of the new methods being investigated to improve the outcomes of patients with inoperable NSCLC. Unfortunately, as shown by prior studies as well as this current report, dose escalation carries a significant risk of normal tissue toxicity. Seven patients out of 38 developed Grade 3-5 late toxicity in this study. However, it should be noted that with only 8 long term survivors, this number may appear lower than would actually be the case. Also, as the median follow up was only 16 months, a report of late toxicity should be taken with caution. Although most of their toxicity was seen in the first 11 months, that is not to say more toxicity would not have been seen with more follow up. Although the TGF-B correlation is interesting, it unfortunately is not protective, as most of patients developing late toxicity were in the 73.6 Gy group. In other words, when TGF-B was investigated, the damage had already been done. With this toxicity, and the fact that there has not been increased efficacy of dose escalation over more traditional chemoradiation, dose escalation should only be attempted in a controlled setting in a clinical trial.

Oncolink's ASTRO Coverage made possible by an unrestricted Educational Grant from Ortho Biotech.